US9475813B2 - Tricyclic pyrrolopyridine compound, and JAK inhibitor - Google Patents

Tricyclic pyrrolopyridine compound, and JAK inhibitor Download PDF

Info

Publication number
US9475813B2
US9475813B2 US14/764,652 US201414764652A US9475813B2 US 9475813 B2 US9475813 B2 US 9475813B2 US 201414764652 A US201414764652 A US 201414764652A US 9475813 B2 US9475813 B2 US 9475813B2
Authority
US
United States
Prior art keywords
group
methyl
mmol
pyrrolo
trans
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
US14/764,652
Other languages
English (en)
Other versions
US20150368245A1 (en
Inventor
Keiji Takahashi
Tsuneo Watanabe
Keishi Hayashi
Kazunori Kurihara
Takanori Nakamura
Akio Yamamoto
Takuya Nishimura
Toshihiko KAMIYAMA
Yuuki HIDAKA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nissan Chemical Corp
Original Assignee
Nissan Chemical Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nissan Chemical Corp filed Critical Nissan Chemical Corp
Assigned to NISSAN CHEMICAL INDUSTRIES, LTD. reassignment NISSAN CHEMICAL INDUSTRIES, LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HIDAKA, Yuuki, NAKAMURA, TAKANORI, HAYASHI, KEISHI, KAMIYAMA, Toshihiko, KURIHARA, KAZUNORI, NISHIMURA, TAKUYA, TAKAHASHI, KEIJI, WATANABE, TSUNEO, YAMAMOTO, AKIO
Publication of US20150368245A1 publication Critical patent/US20150368245A1/en
Application granted granted Critical
Publication of US9475813B2 publication Critical patent/US9475813B2/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to novel tricyclic pyrrolopyridine compounds having a JAK inhibitory effect.
  • JAK Japanese kinase
  • JAK3 tyrosine kinase 2
  • Tyk2 tyrosine kinase 2
  • JAK3 While the kinases of this family, except for JAK3, are widely expressed in tissues, the expression of JAK3 is restricted to immune cells. This does not conflict with that JAK3 plays an important role in signaling via various receptors for IL (interleukin)-2, IL-4, IL-7, IL-9, IL-15, IL-21, etc., by being non-covalently associated with the common ⁇ chain (Non-Patent Documents 1 and 2).
  • XSCID X-linked severe combined immune deficiency
  • JAK1 knockout mice and JAK1 deficient cells indicate that JAK1 relates to signaling via various receptors for IFN (interferon) ⁇ , IFN ⁇ , IFN ⁇ , IL-2, IL-4, IL-6, IL-7, IL-15, etc. (Non-Patent Document 5). Accordingly, by controlling inflammatory responses via such signaling, treatment of diseases relating to activation of macrophages or lymphocytes such as autoimmune diseases and acute and chronic organ transplant rejection is expected.
  • JAK2 relates to signaling via various receptors for EPO (erythropoietin), thrombopoietin, IFN ⁇ , IL-3, GM-CSF, etc.
  • EPO erythropoietin
  • thrombopoietin IFN ⁇
  • IL-3 IL-3
  • GM-CSF GM-CSF
  • Non-Patent Documents 9 and 10 which is a JAK inhibitor have an effect to improve the clinical condition of rheumatoid arthritis and psoriasis in clinical trials (Non-Patent Documents 9 and 10) and has an effect to suppress rejection in monkey renal transplantation models and airway inflammation in mouse asthma models (Non-Patent Documents 11 and 12). From these findings, suppression of immune activity by a JAK inhibitor is considered to be advantageous for prevention or treatment of organ transplant rejection, graft versus host reaction after transplantation, autoimmune diseases and allergic diseases.
  • Compounds having a JAK inhibitory effect other than CP-690,550 are known e.g. in the following reports (for example, Patent Documents 1 to 14), and further development of pharmaceutical agents has been desired.
  • Patent Document 15 In a patent document published after filing of the application on the basis of which the priority of the present application is claimed, tricyclic pyrrolopyridine compounds having a JAK inhibitory effect are reported, however, the patent document failed to specifically disclose the compounds of the present invention (Patent Document 15).
  • the object of the present invention is to provide novel pharmaceutical compounds which have an excellent JAK inhibitory activity and are useful for prevention or treatment of autoimmune diseases, inflammatory diseases and allergic diseases.
  • the present inventors have conducted extensive studies to find a novel low molecular weight compounds having a JAK inhibitory activity and as a result, found that the compounds of the present invention have a high inhibitory effect and accomplished the present invention. That is, the present invention provides the following.
  • R 1 is a hydrogen atom, a C 3-6 cycloalkyl group, a 4 to 7-membered non-aromatic heterocyclic group, a C 1-6 haloalkyl group, or a C 1-6 alkyl group (the C 1-6 alkyl group is not substituted or is substituted with one hydroxy group, cyano group, C 1-6 alkoxy group, C 1-6 alkylthio group, C 1-6 alkylsulfonyl group, carboxy group, carbamoyl group, mono-C 1-6 alkylaminocarbonyl group, di-C 1-6 alkylaminocarbonyl group, C 3-6 cycloalkyl group or 4 to 7-membered non-aromatic heterocyclic group), each of R 2 and R 3 is independently a hydrogen atom, or a C 1-6 alkyl
  • each of R a and R e is independently a hydrogen atom, a C 1-6 alkyl group, a cyano-substituted C 1-6 alkyl group, a C 1-6 alkylsulfonyl-substituted C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 3-6 cycloalkyl group, a cyano-substituted C 3-6 cycloalkyl group, or a C 1-6 haloalkyl-substituted C 3-6 cycloalkyl group
  • each of R b and R c is independently a hydrogen atom, a C 1-6 alkyl group, or a C 1-6 haloalkyl group
  • R d is a C 1-6 alkyl group, a cyano-substituted C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 3-6 cycloalkyl group,
  • R 1 is a C 1-3 haloalkyl group, a C 3-6 cycloalkyl group, or a C 1-3 alkyl group (the C 1-3 alkyl group is not substituted or is substituted with one cyano group, C 1-3 alkoxy group, C 1-3 alkylthio group, di-C 1-3 alkylaminocarbonyl group, C 3-6 cycloalkyl group or tetrahydrofuranyl group).
  • R a is a C 1-3 alkyl group, a cyano-substituted C 1-3 alkyl group, a C 1-3 haloalkyl group, a C 3-6 cycloalkyl group, a cyano-substituted C 3-6 cycloalkyl group, or a C 1-3 haloalkyl-substituted C 3-6 cycloalkyl group, each of R b and R c is independently a hydrogen atom, or a C 1-3 alkyl group, R d is a C 1-3 alkyl group, a C 1-3 haloalkyl group, or a C 3-6 cycloalkyl group, R e is a hydrogen atom, or a cyano-substituted C 1-3 alkyl group, R f is a halogen atom, or a hydroxy group, R g is a cyano-substituted C 1-3 alkyl group, X
  • R a is a methyl group, a cyanomethyl group, a 2,2,2-trifluoroethyl group, a 2,2-difluoroethyl group, a 2-bromo-2,2-difluoroethyl group, a cyclopropyl group, a 1-cyanocycloproyl group or a 1-trifluoromethylcyclopropyl group, each of R b and R c is independently a hydrogen atom or a methyl group, R d is a methyl group, a 2,2,2-trifluoroethyl group or a cyclopropyl group, and R e is a hydrogen atom or a 2-cyanoethyl group. (10) A compound represented by any one of the following chemical structural formulae, a tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof:
  • a preventing, therapeutic and/or alleviating agent for diseases against which a JAK inhibitory effect is effective which contains the JAK inhibitor as defined in (11) as an active ingredient.
  • a therapeutic agent for rheumatoid arthritis which contains the JAK inhibitor as defined in (11) as an active ingredient.
  • novel tricyclic pyrrolopyridine compounds which have an excellent JAK inhibitory effect and are useful for prevention or treatment of particularly autoimmune diseases, inflammatory diseases and allergic diseases.
  • n- denotes normal, “i-” denotes iso, “s-” and “sec-” denote secondary, “t-” and “tert-” denote tertiary, “c-” denotes cyclo, “o-” denotes ortho, “m-” denotes meta, “p-” denotes para, “cis-” denotes a cis-isomer, “trans-” denotes a trans-isomer, “(E)-” denotes an E-isomer, “(Z)-” denotes a Z-isomer, “rac-” and “racemate” denotes racemate, “diastereomixture” denotes a mixture of diastereomers, “Ph” denotes phenyl, “Py” denotes pyridyl, “Me” denotes methyl, “Et” denotes ethyl, “Pr” denotes propyl
  • a halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • a C 1-3 alkyl group means a methyl group, an ethyl group, a propyl group or an isopropyl group.
  • a C 1-6 alkyl group means a linear or branched alkyl group containing one to six carbon atoms, such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a t-butyl group, a n-pentyl group or a n-hexyl group.
  • a C 1-3 haloalkyl group means the above-defined “C 1-3 alkyl group” which is substituted with one or more halogen atom(s) which may be identical with or different from one another selected from a group of substituents consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, at optional position(s).
  • a C 1-6 haloalkyl group means the above-defined “C 1-6 alkyl group” which is substituted with one or more halogen atom(s) which may be identical with or different from one another selected from a group of substituents consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, at optional position(s).
  • C 3-11 cycloalkane means a monocyclic, fused cyclic, bridged cyclic or spirocyclic aliphatic hydrocarbon ring containing 3 to 11 ring-constituting carbon atoms, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, adamantane, bicyclo[3.1.0]octane, bicyclo[2.2.1]heptane or spiro[5.5]undecane.
  • a C 3-11 cycloalkyl group means a monovalent substituent having one hydrogen atom at an optional position removed from the above-defined “C 3-11 cycloalkane”.
  • C 3-6 cycloalkane means one having from 3 to 6 ring-constituting carbon atoms among the above-defined “C 3-11 cycloalkane”, such as cyclopropane, cyclobutane, cyclopentane or cyclohexane.
  • a C 3-6 cycloalkyl group means one having from 3 to 6 ring-constituting carbon atoms among the above-defined “C 3-11 cycloalkyl group”, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • C 4-7 cycloalkane means one having from 4 to 7 ring-constituting carbon atoms among the above-defined “C 3-11 cycloalkane”, such as cyclobutane, cyclopentane, cyclohexane or cycloheptane.
  • a C 1-6 alkoxy group means a linear or branched alkyl group containing one to six carbon atoms, such as a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a t-butoxy group, a n-pentyloxy group or a n-hexyloxy group.
  • a C 1-3 alkoxy group means a methoxy group, an ethoxy group, a n-propoxy group or an i-propoxy group.
  • a C 1-6 alkylene group means a bivalent substituent having one hydrogen atom at an optional position removed from the above-defined “C 1-6 alkyl group”, such as a methylene group, an ethylene group, a propane-1,3-diyl group, a propane-1,2-diyl group, a 2,2-dimethyl-propane-1,3-diyl group, a hexane-1,6-diyl group or a 3-methylbutane-1,2-diyl group.
  • a C 1-3 alkylene group means a methylene group, an ethylene group, a propane-1,3-diyl group or a propane-1,2-diyl group.
  • a C 1-6 haloalkylene group means the above-defined “C 1-6 alkylene group” substituted with one or more halogen atoms which may be identical with or different from one another selected from a group of substituents consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, at optional position(s).
  • a C 1-3 haloalkylene group means the above-defined “C 1-3 alkylene group” substituted with one or more halogen atoms which may be identical with or different from one another selected from a group of substituents consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, at optional position(s).
  • a 4 to 7-membered non-aromatic heterocyclic ring means a monocyclic non-aromatic heterocyclic ring such that
  • hetero atom means a nitrogen atom, an oxygen atom or a sulfur atom
  • the hetero atom means a nitrogen atom, an oxygen atom or a sulfur atom
  • the sulfur atom may be in a sulfinyl group or a sulfonyl group,
  • azetidine such as azetidine, pyrrolidine, pyrrolidinone, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperazine, piperazinone, piperidine, piperidinone, morpholine, thiomorpholine, azepine, diazepine, oxetane, tetrahydrofuran, 1,3-dioxolane, tetrahydropyran, 1,4-dioxane, oxepane or homomorpholine.
  • a 4 to 7-membered non-aromatic heterocyclic group means a monovalent substituent having one hydrogen atom at an optional position removed from the above-defined “4 to 7-membered non-aromatic heterocyclic ring”.
  • the site of bonding is not particularly limited and is optional.
  • a C 1-6 alkylthio group means a group having one of the above “C 1-6 alkyl group” bonded to a sulfur atom, such as a methylthio group, an ethylthio group, a n-propylthio group, an isopropylthio group, a n-butylthio group, an isobutylthio group, a t-butylthio group, a n-pentylthio group or a n-hexylthio group.
  • a C 1-3 alkylthio group means a group having one of the above “C 1-3 alkyl group” bonded to a sulfur atom, such as a methylthio group, an ethylthio group, a n-propylthio group or an isopropylthio group.
  • a C 1-6 alkylsulfonyl group means a group having one of the above “C 1-6 alkyl group” bonded to a sulfonyl group, such as a methylsulfonyl group, an ethylsulfonyl group, a n-propylsulfonyl group, an isopropylsulfonyl group, a n-butylsulfonyl group, an isobutylsulfonyl group, a t-butylsulfonyl group, a n-pentylsulfonyl group or a n-hexylsulfonyl group.
  • a C 1-3 alkylsulfonyl group means a group having one of the above “C 1-3 alkyl group” bonded to a sulfonyl group, such as a methylsulfonyl group, an ethylsulfonyl group, a n-propylsulfonyl group or an i-propylsulfonyl group.
  • a mono-C 1-6 alkylamino group means a group having one of the above “C 1-6 alkyl group” bonded to an amino group, such as a methylamino group, an ethylamino group, a n-propylamino group, an isopropylamino group, a n-butylamino group, an isobutylamino group, a t-butylamino group, n-pentylamino group or a n-hexylamino group.
  • a mono-C 1-3 alkylamino group means a methylamino group, an ethylamino group, a n-propylamino group or an isopropylamino group.
  • a di-C 1-6 alkylamino group means a group having two of the above “C 1-6 alkyl groups” which may be identical with or different from each other bonded to an amino group, such as a dimethylamino group, a diethylamino group, a di-n-propylamino group, a diisopropylamino group, a di-n-butylamino group, a diisobutylamino group, a di-t-butylamino group, a di-n-pentylamino group, a di-n-hexylamino group, an N-ethyl-N-methylamino group, an N-methyl-N-n-propylamino group, an N-isopropyl-N-methylamino group, an N-n-butyl-N-methylamino group, an N-isobutyl-N-methylamino group, an N-t-butyl-N-
  • a di-C 1-3 alkylamino group means a dimethylamino group, a diethylamino group, a di-n-propylamino group, a diisopropylamino group, an N-ethyl-N-methylamino group, an N-methyl-N-n-propylamino group, an N-isopropyl-N-methylamino group, an N-ethyl-N-n-propylamino group or an N-ethyl-N-isopropylamino group.
  • a mono C 1-6 alkylaminocarbonyl group means a group having one of the above “mono C 1-6 alkylamino group” bonded to a carbonyl group, such as a methylaminocarbonyl group, an ethylaminocarbonyl group, a n-propylaminocarbonyl group, an isopropylaminocarbonyl group, a n-butylaminocarbonyl group, an isobutylaminocarbonyl group, a t-butylaminocarbonyl group, a n-pentylaminocarbonyl group or a n-hexylaminocarbonyl group.
  • a mono-C 1-3 alkylaminocarbonyl group means a methylaminocarbonyl group, an ethylaminocarbonyl group, a n-propylaminocarbonyl group or an isopropylaminocarbonyl group.
  • a di-C 1-6 alkylaminocarbonyl group means a group having one of the above “di-C 1-6 alkylamino group” bonded to a carbonyl group, such as a dimethylaminocarbonyl group, a diethylaminocarbonyl group, a di-n-propylaminocarbonyl group, a diisopropylaminocarbonyl group, a di-n-butylaminocarbonyl group, a diisobutylaminocarbonyl group, a di-t-butylaminocarbonyl group, a di-n-pentylaminocarbonyl group, a di-n-hexylaminocarbonyl group, an N-ethyl-N-methylaminocarbonyl group, an N-methyl-N-n-propylaminocarbonyl group, an N-isopropyl-N-methylaminocarbonyl group, an N-n-butyl
  • a di-C 1-3 alkylaminocarbonyl group means a dimethylaminocarbonyl group, a diethylaminocarbonyl group, a di-n-propylaminocarbonyl group, a diisopropylaminocarbonyl group, an N-ethyl-N-methylaminocarbonyl group, an N-methyl-N-n-propylaminocarbonyl group, an N-isopropyl-N-methylaminocarbonyl group, an N-ethyl-N-n-propylaminocarbonyl group or an N-ethyl-N-isopropylaminocarbonyl group.
  • a cyano-substituted C 1-6 alkyl group means the above-defined “C 1-6 alkyl group” substituted with one or more cyano group(s) at optional position(s).
  • a cyano-substituted C 1-3 alkyl group means the above-defined “C 1-3 alkyl group” substituted with one or more cyano group(s) at optional position(s).
  • a C 1-6 alkylsulfonyl-substituted C 1-6 alkyl group means the above-defined “C 1-6 alkyl group” substituted with one or more of the above-defined “C 1-6 alkylsulfonyl group(s)” at optional position(s).
  • a C 1-3 alkylsulfonyl-substituted C 1-3 alkyl group means the above-defined “C 1-3 alkyl group” substituted with one of the above-defined “C 1-3 alkylsulfonyl group” at an optional position.
  • a cyano-substituted C 3-6 cycloalkyl group means the above-defined “C 3-6 cycloalkyl group” substituted with one or more cyano group(s) at optional position(s).
  • a C 1-6 haloalkyl-substituted C 3-6 cycloalkyl group means the above-defined “C 3-6 cycloalkyl group” substituted with one or more of the above-defined “C 1-6 haloalkyl group(s)” at optional position(s).
  • a C 1-3 haloalkyl-substituted C 3-6 cycloalkyl group means the above-defined “C 3-6 cycloalkyl group” substituted with one or more of the above-defined “C 1-3 haloalkyl group(s)” at optional position(s).
  • the substitute R 1 is preferably a hydrogen atom
  • the C 1-3 alkyl group is not substituted or is substituted with one cyano group, methoxy group, methylthio group, dimethylaminocarbonyl group, cyclopropyl group or tetrahydrofuran-2-yl group).
  • the substituted R 1 is more preferably a C 1-3 haloalkyl group
  • the C 1-3 alkyl group is not substituted or is substituted with one cyano group, methoxy group, methylthio group, dimethylaminocarbonyl group, cyclopropyl group or tetrahydrofuran-2-yl group).
  • the substituent R 1 is further preferably a methyl group
  • the substituents R 2 and R 3 are preferably a hydrogen atom.
  • the ring A is preferably C 4-7 cycloalkane.
  • the ring A is more preferably cyclohexane.
  • a C 1-3 alkylene group may be mentioned.
  • the C 1-3 alkylene group is more preferably a methylene group.
  • a C 1-3 haloalkylene group may be mentioned.
  • the C 1-3 haloalkylene group is more preferably a fluoromethylene group or a difluoromethylene group.
  • a hydrogen atom may be mentioned.
  • a halogen atom may be mentioned.
  • NR a R b NR c S( ⁇ O) 2 R d , or OR e may be mentioned.
  • the substituent R a is preferably a C 1-3 alkyl group
  • the substituent R a is more preferably a methyl group
  • the substituent R b is preferably a hydrogen atom or a C 1-3 alkyl group.
  • the substituent R b is more preferably a hydrogen atom or a methyl group.
  • the substituent R c is preferably a hydrogen atom or a C 1-3 alkyl group.
  • the substituent R c is more preferably a hydrogen atom or a methyl group.
  • the substituent R d is preferably a C 1-3 alkyl group
  • the substituent R d is more preferably a methyl group
  • the substituent R e is preferably a hydrogen atom or a cyano-substituted C 1-3 alkyl group.
  • the substituent R e is more preferably a hydrogen atom or a 2-cyanoethyl group.
  • the substituent R f is preferably a halogen atom or a hydroxy group.
  • the substituent R g is preferably a cyano-substituted C 1-3 alkyl group.
  • the substituent R g is more preferably a 2-cyanoethyl group.
  • the substituent X a is preferably S( ⁇ O) 2 or CH 2 .
  • the substituent X b is preferably CH 2 .
  • n is preferably 0 or 1.
  • m is preferably 0 or 1.
  • a preferred example of the structure of the compound of the present invention may be mentioned by combining the above-described preferred substituents in the structure of the formula (I).
  • the following may be mentioned.
  • R 1 is a hydrogen atom, a C 3-6 cycloalkyl group, a C 1-3 haloalkyl group, or a C 1-3 alkyl group (the C 1-3 alkyl group is not substituted or is substituted with one hydroxy group, cyano group, C 1-3 alkoxy group, C 1-3 alkylthio group, C 1-3 alkylsulfonyl group, carboxy group, carbamoyl group, mono-C 1-3 alkylaminocarbonyl group, di-C 1-3 alkylaminocarbonyl group, C 3-6 cycloalkyl group or 4 to 7-membered non-aromatic heterocyclic group), each of R 2 and R 3 is independently a hydrogen atom, or a C 1-3 alkyl group, L 1 is a single bond, a C 1-3 alkylene group, or a C 1-3 haloalkylene group, R 4 is a hydrogen
  • each of R a and R e is independently a hydrogen atom, a C 1-3 alkyl group, a cyano-substituted C 1-3 alkyl group, a C 1-3 alkylsulfonyl-substituted C 1-3 alkyl group, a C 1-3 haloalkyl group, a C 3-6 cycloalkyl group, a cyano-substituted C 3-6 cycloalkyl group, or a C 1-3 haloalkyl-substituted C 3-6 cycloalkyl group
  • each of R b and R c is independently a hydrogen atom, a C 1-3 alkyl group, or a C 1-3 haloalkyl group
  • R d is a C 1-3 alkyl group, a cyano-substituted C 1-3 alkyl group, a C 1-3 haloalkyl group, a C 3-6 cycloalkyl group,
  • a JAK inhibitor which contains the compound, a tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof as defined in any one of the above 1) to 13) as an active ingredient.
  • a preventing, therapeutic or alleviating agent for diseases against which a JAK inhibitory effect is effective which contains the JAK inhibitor as defined in the above 14) as an active ingredient.
  • a therapeutic agent for rheumatoid arthritis which contains the JAK inhibitor as defined in the above 14) as an active ingredient.
  • a pharmaceutical agent which contains the compound, a tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof as defined in any one of the above 1) to 13) as an active ingredient.
  • the compounds of the present invention may be prepared by the following process, however, the following production process is an example of a common production process, and the process is not limited to the following production process.
  • the compounds of the present invention can be usually purified by column chromatography, thin-layer chromatography, high performance liquid chromatography (HPLC), high performance liquid chromatography/mass spectrometry (LC/MS) or the like and as the case requires, compounds with higher purity may be obtained by recrystallization or washing with a solvent.
  • HPLC high performance liquid chromatography
  • LC/MS high performance liquid chromatography/mass spectrometry
  • the solvent is not particularly limited so long as it is stable under the reaction conditions and is inert to the reaction, and may, for example, be a sulfoxide type solvent (such as dimethylsulfoxide), an amide type solvent (such as N,N-dimethylformamide or N,N-dimethylacetamide), an ether type solvent (such as ethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane or cyclopentyl methyl ether), a halogen type solvent (such as dichloromethane, chloroform or 1,2-dichlorothene), a nitrile type solvent (such as acetonitrile or propionitrile), an aromatic hydrocarbon type solvent (such as benzene or toluene), an aliphatic hydrocarbon type solvent (such as hexane or heptane), an ester type solvent (
  • a sulfoxide type solvent such as dimethyl
  • the compounds may be used in equivalent amounts, or a specific compound may be used in excess.
  • the reaction temperature may be properly set within a range of from ⁇ 78° C. to the boiling point of the solvent used for the reaction, and the present production process may be carried out under normal pressure, under elevated pressure, under irradiation with microwaves, etc.
  • reaction under irradiation with microwaves is effective in some cases so as to allow the reaction to proceed smoothly.
  • An acid to be used in the common process for producing the compounds of the present invention may, for example, be an organic acid (such as acetic acid, trifluoroacetic acid or p-toluenesulfonic acid) or an inorganic acid (such as sulfuric acid or hydrochloric acid).
  • an organic acid such as acetic acid, trifluoroacetic acid or p-toluenesulfonic acid
  • an inorganic acid such as sulfuric acid or hydrochloric acid
  • reaction in the presence of an acid is effective in some cases so as to allow the reaction to proceed smoothly.
  • reaction in the presence of an acid catalyst such as ytterbium(III) trifluoromethanesulfonate or scandium(III) trifluoromethanesulfonate is effective in some cases so as to allow the reaction to proceed smoothly.
  • a base to be used in the common process for producing the compounds of the present invention may, for example, be an organic metal compound (such as n-butyllithium, s-butyllithium, lithium diisopropylamide or isopropylmagnesium bromide), an organic base (such as triethylamine, N,N-diisopropylethylamine or N,N-dimethylaminopyridine) or an inorganic base (such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide or sodium hydride).
  • an organic metal compound such as n-butyllithium, s-butyllithium, lithium diisopropylamide or isopropylmagnesium bromide
  • an organic base such as triethylamine, N,N-diisopropylethylamine or N,N-dimethylaminopyridine
  • an inorganic base such as sodium carbonate, potassium carbonate, ces
  • reaction in the presence of a base is preferred in some cases so as to allow the reaction to proceed smoothly.
  • a derivative protected by a protecting group means a compound which may be induced to a desired product by hydrolysis, reduction, oxidation, alkylation or the like as the case requires, and includes a compound protected by a protecting group acceptable in terms of synthetic organic chemistry.
  • Protection and deprotection may be carried out using a known protecting group by a protection/deprotection reaction (for example, Protective Groups in Organic Synthesis, Fourth edition, T. W. Greene, John Wiley & Sons Inc., 2006).
  • a protection/deprotection reaction for example, Protective Groups in Organic Synthesis, Fourth edition, T. W. Greene, John Wiley & Sons Inc., 2006.
  • Hydrolysis, reduction and oxidation may be carried out by a known functional group conversion method (for example, Comprehensive Organic Transformations, Second Edition, R. C. Larock, Wiley-VCH, 1999).
  • compounds (1)-8, (1)-9, (1)-11 and (1)-12 may be produced, for example, by the following reaction scheme (in the scheme, PG 1 represents a hydrogen atom or a protecting group such as a Ts group, a TIPS group or a SEM group, and the other symbols are as defined above):
  • Compound (1)-2 is obtained by carrying out lithiation at ⁇ 78° C. to room temperature using compound (1)-1 and an organic metal reagent such as n-butyllithium or s-butyllithium, and then reacting N,N-dimethylformamide.
  • Compound (1)-3 may be synthesized at room temperature to the refluxing temperature using compound (1)-2 and an oxidizing agent such as potassium permanganate or sodium chlorite.
  • Compound (1)-4 may be synthesized by forming an acid chloride at 0° C. to the refluxing temperature using compound (1)-3 and thionyl chloride or phosphorus oxychloride, followed by reaction at 0° C. to the refluxing temperature using ammonia/methanol or its equivalent.
  • Compound (1)-6 may be synthesized at room temperature to the refluxing temperature using compound (1)-4 and amine derivative (1)-5. Further, it may be prepared also under reaction conditions used for Buchwald-Hartwig reaction (for example, Advanced Synthesis & Catalysis, 2000, 346, pp. 1599-1626).
  • the metal species and the ligand used in the reaction are not particularly limited, and tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0), palladium(II) acetate or the like and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) or the like may properly be combined.
  • Compound (1)-7 may be synthesized at room temperature to the refluxing temperature using compound (1)-6 and R 2 CO 2 R Q , R 2 C(OR Q ) 3 or the like (R Q is a hydrogen atom or a C 1-6 alkyl group).
  • Compound (1)-8 may be synthesized at 0° C. to the refluxing temperature using compound (1)-7 and a reducing agent such as sodium borohydride.
  • Compound (1)-11 may be synthesized at room temperature to the refluxing temperature using compound (1)-6 and carbonyl compound (1)-10.
  • Compounds (1)-9 and (1)-12 may be synthesized at ⁇ 78° C. to the refluxing temperature using compound (1)-8 or (1)-11, an electrophile represented by R 1 -R L (R L is a leaving group such as a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group, and R 1 -R L may, for example, be an alkyl halide, a methanesulfonate or an acid halide) and a base such as potassium carbonate or sodium hydroxide.
  • R 1 -R L R L is a leaving group such as a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group
  • R 1 -R L may, for example, be an alkyl halide, a methanesulfonate or an acid halide
  • a base such as potassium carbonate
  • Compounds (1)-8, (1)-9, (1)-11 and (1)-12 wherein PG 1 is a protecting group may further be subjected to deprotection to obtain the corresponding compounds wherein PG 1 is a hydrogen atom.
  • compounds (2)-8, (2)-10 and (2)-11 may be produced, for example, by the following reaction scheme (in the scheme, PG 1 represents a hydrogen atom or a protecting group such as a Ts group, a TIPS group or a SEM group, PG 2 represents a protecting group such as a TIPS group or a TBS group, and the other symbols are as defined above):
  • Compound (2)-2 may be synthesized at room temperature to the refluxing temperature using compounds (1)-6 and (2)-1.
  • Compound (2)-3 may be synthesized by protecting the hydroxy group of compound (2)-2 with PG 2 , followed by reaction at room temperature to the refluxing temperature using methyl orthoformate or its equivalent.
  • Compound (2)-4 may be synthesized at 0° C. to the refluxing temperature using compound (2)-3 and a reducing agent such as sodium borohydride.
  • Compound (2)-5 may be synthesized by alkylation at ⁇ 78° C. to the refluxing temperature using compound (2)-4, an electrophile represented by R 1 -R L (R L is a leaving group such as a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group, and R 1 -R L may, for example, be an alkyl halide, a methanesulfonate or an acid halide) and a base such as potassium carbonate or sodium hydroxide, followed by deprotection of PG 2 .
  • R 1 -R L R L is a leaving group such as a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group
  • R 1 -R L may, for example, be an alkyl halide, a methanesulfonate or an acid halide
  • Compound (2)-6 may be synthesized at ⁇ 78° C. to the refluxing temperature using compound (2)-5 and an oxidizing agent such as 2-iodoxybenzoic acid or pyridinium chlorochromate.
  • Compound (2)-8 may be synthesized at room temperature to the refluxing temperature using compound (2)-6, compound (2)-7 and a reducing agent such as 2-picoline borane or sodium triacetoxyborohydride.
  • Compound (2)-10 may be synthesized at ⁇ 78° C. to the refluxing temperature using compound (2)-8 wherein R a is a hydrogen atom and sulfonyl chloride (2)-9 with a base such as potassium carbonate or triethylamine.
  • Compound (2)-11 may be synthesized at ⁇ 78° C. to the refluxing temperature using compound (2)-5, an electrophile such as R e —R L (R L means a leaving group such as a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group, and R e —R L may, for example, be an alkyl halide, a methanesulfonate or an acid halide), an ⁇ , ⁇ unsaturated nitrile compound or an ⁇ , ⁇ unsaturated sulfonyl compound, and a base such as potassium carbonate or sodium carbonate.
  • R e —R L R L means a leaving group such as a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group
  • R e —R L may, for example, be an alkyl
  • Compounds (2)-5, (2)-8 and (2)-10 wherein PG 1 is a protecting group may further be subjected to deprotection to obtain the corresponding compounds wherein PG 1 is a hydrogen atom.
  • the tricyclic pyrrolopyridine compounds represented by the formula (I) may be present in the form of endocyclic or exocyclic tautomers or geometric isomers, their mixtures, or mixtures of the isomers. Further, when the compounds of the present invention have an asymmetric center or have an asymmetric center caused by isomerization, they may be in the form of optical isomers or in the form of mixtures containing them in certain ratios. Further, in the case of compounds having two or more asymmetric centers, diastereomers due to each optical isomerism are present. The compounds of the present invention may be in the form of any one of diastereomers or in the form of any of all such isomers in certain ratios.
  • a diastereomer may be isolated from a mixture of the isomers by a method well known to those skilled in the art, such as fractional crystallization method, and an optically active substance may be also obtained by organic chemical methods known for such a purpose.
  • the tricyclic pyrrolopyridine compounds represented by the formula (I) of the present invention or pharmaceutically acceptable salts thereof may be in the form of arbitrary crystals or arbitrary hydrates, depending on the production conditions.
  • the present invention covers these crystals, hydrates and their mixtures.
  • These compounds may be also in the form of a solvate with an organic solvent such as acetone, ethanol, 1-propanol or 2-propanol, and the present invention covers any of these forms.
  • the present invention covers pharmaceutically acceptable salts of the compounds of the formula (I) of the present invention.
  • the compounds represented by the formula (I) of the present invention may be converted to pharmaceutically acceptable salts or may be dissociated from the resulting salts, if necessary.
  • the pharmaceutically acceptable salt of the present invention may, for example, be a salt with an alkali metal (such as lithium, sodium or potassium), an alkaline earth metal (such as magnesium or calcium), ammonium, an organic base, an amino acid, an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid), or an organic acid (such as acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid or p-toluenesulfonic acid).
  • an alkali metal such as lithium, sodium or potassium
  • an alkaline earth metal such as magnesium or calcium
  • ammonium an organic base
  • an amino acid such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid
  • the present invention also covers prodrugs of the compounds represented by the formula (I) of the present invention.
  • a prodrug is a derivative of a pharmaceutical compound having a chemically or metabolically degradable group and is a compound which is induced into a pharmacologically active compound by degradation upon solvolysis or under physiological conditions in vivo.
  • Methods for selecting or producing appropriate prodrugs are disclosed, for example, in Design of Prodrugs (Elsevier, Amsterdam 1985).
  • an acyloxy derivative obtained by reacting the compound with an appropriate acyl halide an appropriate acid anhydride or an appropriate haloalkoxycarbonyl compound may, for example, be mentioned as a prodrug.
  • Structures particularly preferred as prodrugs include —O—COC 2 H 5 , —O—CO(t-Bu), —O—COC 15 H 31 , —O—CO(m-CO 2 Na-Ph), —O—COCH 2 CH 2 CO 2 Na, —OCOCH(NH 2 )CH 3 , —O—COCH 2 N(CH 3 ) 2 and —O—CH 2 OC( ⁇ O)CH 3 .
  • a prodrug obtained by reacting the compound having a —NH— group with an appropriate acid halide, an appropriate mixed acid anhydride or an appropriate haloalkoxycarbonyl compound may, for example, be mentioned.
  • Structures particularly preferred as prodrugs include —N—CO(CH 2 ) 20 OCH 3 , —N—COCH(NH 2 )CH 3 and —N—CH 2 O(C ⁇ O)CH 3 .
  • the preventing, therapeutic and/or alleviating agent for diseases against which a JAK inhibitory effect is effective which contains the JAK inhibitor of the present invention as an active ingredient, may usually be administered as oral medicines such as tablets, capsules, powder, granules, pills and syrup, as rectal medicines, percutaneous medicines or injections.
  • the agents of the present invention may be administered as a single therapeutic agent or as a mixture with other therapeutic agents. Though they may be administered as they are, they are usually administered in the form of pharmaceutical compositions. These pharmaceutical preparations can be obtained by adding pharmacologically and pharmaceutically acceptable additives by conventional methods.
  • Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs or may be supplied as dry syrups to be mixed with water or other appropriate solvents before use.
  • Such liquid preparations may contain ordinary additives such as suspending agents, perfumes, diluents and emulsifiers. In the case of rectal administration, they may be administered as suppositories.
  • Suppositories may use an appropriate substance such as cacao butter, laurin tallow, Macrogol, glycerogelatin, Witepsol, sodium stearate and mixtures thereof as the base and may, if necessary, contain an emulsifier, a suspending agent, a preservative and the like.
  • pharmaceutical ingredients such as distilled water for injection, physiological saline, 5% glucose solution, propylene glycol and other solvents or solubilizing agents, a pH regulator, an isotonizing agent and a stabilizer may be used to form aqueous dosage forms or dosage forms which need dissolution before use.
  • the dose of the agents of the present invention for administration to human is usually about from 0.1 to 1,000 mg/body/day in the case of oral drugs or rectal administration and about from 0.05 mg to 500 mg/body/day in the case of injections into an adult, though it depends on the age and conditions of the patient.
  • the above-mentioned ranges are mere examples, and the dose should be determined from the conditions of the patient.
  • JAK3-associated diseases are, in addition to rheumatoid arthritis, inflammatory or proliferative dermatoses such as psoriasis, atopic dermatitis, contact dermatitis, eczematoid dermatitis, seborrheic dermatitis, lichen planus, pemphigus, pemphigoid, epidermolysis bullosa, hives, angioedema, angiitis, erythema, dermal eosinophilia, lupus erythematosus, acne, alopecia areata, immune dermatoses, reversible airway obstruction, mucitis and angitis.
  • inflammatory or proliferative dermatoses such as psoriasis, atopic dermatitis, contact dermatitis, eczematoid dermatitis, seborrheic dermatitis, lichen planus, pemphi
  • JAK3- and JAK1-associated diseases are, in addition to rheumatoid arthritis, allergic diseases such as asthma and atopic dermatitis, Alzheimer disease, atherosclerosis, cancer, leukemia, rejection of organ or tissue grafts (such as heart, kidney, liver, bone marrow, skin, horn, lung, pancreas, islet, small intestine, extremities, muscles, nerves, intervertebral disks, trachea, myoblasts and cartilage), graft-versus-host reaction after bone marrow transplantation and autoimmune diseases such as rheumatic disease, systemic lupus erythematosus (SLE), Hashimoto's disease, multiple sclerosis, myasthenia gravis, type I diabetes and diabetic complications.
  • JAK2-associated diseases include, for example, myeloproliferative neoplasms.
  • the compounds of the present invention may be used alone or in combination with one or more pharmaceutical agents such as immunosuppressants, anti-inflammatory agents and antirheumatic agents.
  • the agents which may be combined may, for example, be Cyclosporin A, Tacrolimus, Leflunomide, Deoxyspergualin, Mycophenolate, Azathioprine, Etanercept (e.g. Embrel), Infliximab (e.g. REMICADE), Adalimumab (e.g. HUMIRA), Certolizumab pegol (e.g. CIMZIA), Golimumab (e.g. Simponi), Anakinra (e.g. Kineret), Rituximab (e.g.
  • Tocilizumab e.g. ACTEMRA
  • Methotrexate Aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroid (such as prednisolone or dexamethasone), but there is no restriction.
  • the compound In order that the agent is highly effective for diseases against which a JAK inhibitory effect is effective, particularly for rheumatoid arthritis, the compound more preferably has a favorable inhibitory effect in the whole blood.
  • One of the characteristics of the present invention is to provide a compound having a favorable JAK inhibitory effect in the whole blood.
  • One of the characteristics of the present invention is to provide a JAK inhibitor having favorable oral adsorption properties.
  • NMR nuclear magnetic resonance
  • LC/MS high performance liquid chromatography/mass spectrometry
  • v/v means volume ratio.
  • Rf denotes Reference Synthetic Example
  • Ex denotes Synthetic Example
  • Structure denotes a chemical structural formula
  • diastereomixture denotes a diastereomer mixture
  • racemate denotes a racemic mixture
  • cis/trans mixture denotes a cis- and trans-isomeric mixture
  • E/Z mixture denotes a E- and Z-isomeric mixture
  • Data denotes physical property data
  • condition denotes measurement condition
  • retention time and “R.
  • rac- or “racemate” used in texts or tables for a compound having more than one asymmetric center means that the compound is in the form of a racemic mixture of the compound possessing the specified absolute configuration and its enantiomer.
  • the 1 H-NMR data show chemical shifts ⁇ (unit: ppm) (splitting pattern, value of integral) measured at 300 MHz (with JNM-ECP300, manufactured by JEOL Ltd or JNM-ECX300, manufactured by JEOL Ltd) using tetramethylsilane as an internal standard.
  • Initiator sixty manufactured by Biotage was used as a microwave reactor.
  • LC/MS spectra were measured by using ESI (electrospray ionization).
  • ESI + or “ESI+” denotes ESI-positive mode
  • ESI ⁇ or “ESI ⁇ ” denotes ESI-negative mode.
  • a mixture of Liquids A and B was flown at 0.6 mL/min at a mixing ratio of 90/10 (v/v) for the first 0.5 minute, and then the mixing ratio was linearly changed to 10/90 (v/v) over 2.5 minutes and then maintained at 10/90 (v/v) for 0.7 minute.
  • the mixing ratio and the flow rate were linearly changed to 90/10 (v/v) and 0.8 mL/min, respectively, over 0.1 minute, maintained constant for 1 minute and linearly changed to 90/10 (v/v) and 0.6 mL/min, respectively, over 0.1 minute.
  • a mixture of Liquids A and B was flown at 0.6 mL/min at a mixing ratio of 95/5 (v/v) for the first 0.5 minute, and then the mixing ratio was linearly changed to 40/60 (v/v) over 2.5 minutes and then maintained at 40/60 (v/v) for 0.6 minute.
  • the mixing ratio and the flow rate were linearly changed to 0/100 (v/v) and 0.8 mL/min, respectively, over 0.1 minute, and maintained constant for 0.1 minute.
  • the mixing ratio was linearly changed to 95/5 (v/v) over 0.1 minute and maintained constant for 0.9 minute at a constant flow rate of 0.8 mL/min. Then, the mixing ratio and the flow rate were linearly changed to 90/10 (v/v) and 0.6 mL/min, respectively, over 0.1 minute.
  • the reaction mixture was mixed with 4 M hydrogen chloride in 1,4-dioxane (20 mL), followed by stirring for 30 minutes, and then mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (15 mL), and mixed with trifluoroacetic acid (15 mL), and the mixture was stirred for 1 day. The reaction mixture was concentrated under reduced pressure, mixed with water and neutralized with saturated aqueous sodium hydrogencarbonate, and the precipitated solid was collected by filtration and dried under reduced pressure.
  • trans-4-Aminocyclohexane carboxylic acid (314 mg, 2.19 mmol) was added little by little to a solution of sodium bis(2-methoxyethoxy)aluminum hydride-toluene solution (65 wt %, 3.0 mL) in toluene (3 mL) warmed to 75° C. in advance, and the mixture was stirred for 7 hours.
  • the reaction mixture was allowed to cool to room temperature and mixed with 1M aqueous sodium hydroxide (20 mL), followed by stirring at 80° C. for 10 minutes.
  • the reaction mixture was allowed to cool to room temperature and separated into an aqueous layer and a toluene layer, and the aqueous layer was extracted with chloroform three times.
  • the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound as a white solid (170 mg, yield: 60%).
  • the reaction mixture was allowed to cool to room temperature, mixed with water, acidified with aqueous citric acid, and extracted with ethyl acetate.
  • the organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the resulting yellow solid was washed with ethyl acetate/hexane (1/5 (v/v)) to obtain the title compound as a white solid (21.4 g, yield: 73%).
  • reaction mixture was mixed with water and extracted with ethyl acetate twice. The organic layers were combined, washed with saturated aqueous sodium hydrogencarbonate five times, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting yellow solid was washed with diethyl ether and dried under reduced pressure to obtain the title compound as a white solid (3.08 g, yield: 86%).
  • the reaction mixture was mixed with saturated aqueous ammonium chloride and water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound as a pale yellow solid (524 mg). The resulting pale yellow solid was used for the next step without further purification.
  • the reaction mixture was mixed with water, and extracted with ethyl acetate.
  • the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound as a pale yellow oil (655 mg).
  • the resulting pale yellow oil was used for the next step without further purification.
  • the reaction mixture was mixed with aqueous sodium thiosulfate and saturated aqueous sodium hydrogencarbonate, stirred at room temperature for 30 minutes and extracted with ethyl acetate.
  • the organic layer was washed with aqueous sodium hydrogencarbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate) to obtain a pale yellow oil containing the title compound (155 mg). The resulting pale yellow oil was used for the next step without further purification.
  • the reaction mixture was mixed with 1M aqueous sodium hydroxide and extracted with ethyl acetate.
  • the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel thin-layer chromatography (ethyl acetate) to obtain a colorless oil containing the title compound (21.5 mg).
  • the resulting colorless oil was used for the next step without further purification.
  • the reaction mixture was cooled to ice bath temperature, mixed with saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate.
  • the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the resulting pale yellow oil was used for the next step without further purification.
  • the reaction mixture was cooled to ice bath temperature, mixed with saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate.
  • the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the resulting pale yellow oil was used for the next step without further purification.
  • the reaction mixture was allowed to cool to room temperature, mixed with sodium borohydride (4.95 mg, 0.131 mmol) and stirred for 30 minutes.
  • the reaction mixture was mixed with saturated aqueous ammonium chloride and extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (46.8 mg).
  • the resulting title compound was used for the next step without further purification.
  • the reaction mixture was mixed with saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate.
  • the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the resulting mixture was used for the next step without further purification.
  • the reaction mixture was mixed with saturated aqueous ammonium chloride and extracted with ethyl acetate.
  • the organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the reaction mixture was mixed with aqueous sodium hydrogencarbonate and aqueous sodium thiosulfate, and the mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was extracted with chloroform twice, with a mixed solvent of chloroform/2-propanol (5/1 (v/v)) twice, and with a mixed solvent of chloroform/methanol (10/1 (v/v)) five times.
  • the resulting organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • reaction mixture was mixed with 1M aqueous sodium hydroxide and extracted with ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • reaction mixture was mixed with 1M aqueous sodium hydroxide and extracted with ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • reaction mixture was mixed with 1M aqueous sodium hydroxide and extracted with ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the reaction mixture was mixed with 1M aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a green oil containing the title compound (30.4 mg). The resulting green oil was used for the next step without further purification.
  • reaction mixture was mixed with saturated aqueous ammonium chloride and extracted with chloroform.
  • the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the reaction mixture was mixed with saturated aqueous ammonium chloride and extracted with ethyl acetate.
  • the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • reaction mixture was mixed with water and extracted with ethyl acetate.
  • organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • reaction mixture was mixed with water and extracted with ethyl acetate.
  • organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the reaction mixture was mixed with water and saturated aqueous sodium hydrogencarbonate and extracted with chloroform three times.
  • the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the reaction mixture was mixed with water and aqueous ammonium chloride and extracted with ethyl acetate.
  • the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography to obtain the title compound as a colorless oil (176 mg, yield: 51%).
  • the reaction mixture was mixed with water and extracted with ethyl acetate.
  • the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the title compound was obtained as a colorless oil (29.7 mg, yield: 82%) substantially in the same manner as in Reference Synthetic Example 54 except that cyclopropanesulfonyl chloride was used instead of methanesulfonyl chloride.
  • the title compound was obtained as a colorless amorphous substance (18.0 mg, yield: 43%) substantially in the same manner as in Reference Synthetic Example 30 except that cyclopropylamine was used instead of 2,2,2-trifluoroethylamine.
  • the title compound was obtained as a colorless oil (30.5 mg, yield: 93%) substantially in the same manner as in Reference Synthetic Example 46 except that (bromomethyl)cyclopropane was used instead of 1-bromo-2-methoxyethane.
  • the title compound was obtained as a colorless oil (20.7 mg, yield: 61%) substantially in the same manner as in Reference Synthetic Example 46 except that 2-(bromomethyl)tetrahydrofuran was used instead of 1-bromo-2-methoxyethane.
  • the title compound was obtained as a colorless oil (34.3 mg, yield: 78%) substantially in the same manner as in Reference Synthetic Example 46 except that 4-bromobutyronitrile was used instead of 1-bromo-2-methoxyethane.
  • the title compound was obtained as a colorless oil (42.3 mg, yield: 81%) substantially in the same manner as in Reference Synthetic Example 46 except that ethyl iodide was used instead of 1-bromo-2-methoxyethane.
  • the reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • sodium hydride 55 wt % dispersion in liquid paraffin, 4.2 mg, 0.097 mmol
  • the mixture was stirred at room temperature for 24 hours.
  • sodium hydride 55 wt % dispersion in liquid paraffin, 4.2 mg, 0.097 mmol
  • 1,8-diazabicyclo[5.4.0]undec-7-ene (9.7 ⁇ L, 0.065 mmol) was added, and the mixture was stirred at room temperature for 24 hours. Additional amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.019 mL, 0.13 mmol) was added, and the mixture was stirred at room temperature for 4 days. Additional amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.095 mL, 0.65 mmol) was added again, and the mixture was stirred at room temperature for 2 days. The reaction mixture was mixed with water and aqueous ammonium chloride and extracted with ethyl acetate.
  • the title compound was obtained as a colorless oil (34.2 mg, yield: 52%) substantially in the same manner as in Reference Synthetic Example 46 except that ethyl bromoacetate was used instead of 1-bromo-2-methoxyethane.
  • the reaction mixture was mixed with water and saturated aqueous ammonium chloride and extracted with chloroform.
  • the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the title compound was obtained as a pale brown oil (206 mg, yield: 96%) substantially in the same manner as in Reference Synthetic Example 27 except that bromoacetonitrile was used instead of methyl iodide.
  • reaction mixture was mixed with saturated aqueous ammonium chloride and extracted with chloroform.
  • the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • reaction mixture was mixed with water and extracted with ethyl acetate.
  • organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • reaction mixture was mixed with water and extracted with ethyl acetate.
  • organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the reaction mixture was mixed with 1M aqueous sodium hydroxide and extracted with ethyl acetate.
  • the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the reaction mixture was mixed with saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate.
  • the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • reaction mixture was mixed with 1M aqueous sodium hydroxide and extracted with ethyl acetate.
  • the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound as a pale yellow oil (21.0 mg, yield: 50%).
  • the reaction mixture was mixed with aqueous sodium hydrogencarbonate and extracted with ethyl acetate.
  • the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the reaction mixture was mixed with saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate.
  • the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the reaction mixture was mixed with 1M hydrochloric acid and separated with ethyl acetate.
  • the aqueous layer was basified with 1M aqueous sodium hydroxide and extracted with ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • reaction mixture was mixed with water and extracted with ethyl acetate.
  • organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a mixture containing the title compound (227 mg, a mixture with triphenylphosphine oxide).
  • reaction mixture was mixed with water and extracted with ethyl acetate.
  • organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a mixture containing the title compound (280 mg, a mixture with triphenylphosphine oxide).
  • the title compound was obtained as a colorless oil (35.0 mg, yield: 99%) substantially in the same manner as in Reference Synthetic Example 24 except that (S)-3-fluoropyrrolidine was used instead of 2-bromo-2,2-difluoroethylamine hydrochloride.
  • reaction mixture was mixed with water and extracted with ethyl acetate.
  • organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound as a colorless oil (31.9 mg, yield: 95%).
  • the reaction mixture was mixed with saturated aqueous ammonium and extracted with ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • reaction mixture was mixed with water and extracted with ethyl acetate.
  • organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • reaction mixture was mixed with water and saturated aqueous ammonium chloride and extracted with chloroform three times.
  • the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the title compound was obtained as a colorless oil (36.0 mg, yield: 63%) substantially in the same manner as in Reference Synthetic Example 30 except that 1-aminocyclopropanecarbonitrile hydrochloride was used instead of 2,2,2-trifluoroethylamine.
  • reaction mixture was mixed with water and extracted with ethyl acetate.
  • organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the title compound was obtained as a colorless oil (30.1 mg, yield: 70%) substantially in the same manner as in Reference Synthetic Example 30 except that 1-(trifluoromethyl)cyclopropanamine was used instead of 2,2,2-trifluoroethylamine.
  • the title compound was obtained as a colorless oil (30.0 mg, yield: 86%) substantially in the same manner as in Reference Synthetic Example 86 except that methylaminoacetonitrile hydrochloride was used instead of aminoacetonitrile hydrochloride.
  • the title compound was obtained as a colorless oil (30.0 mg, yield: 75%) substantially in the same manner as in Reference Synthetic Example 87 except that methylaminoacetonitrile hydrochloride was used instead of aminoacetonitrile hydrochloride.
  • the reaction mixture was mixed with acetic acid (0.1 mL) and stirred at room temperature for 1.5 hours.
  • the reaction mixture was mixed with 1M hydrochloric acid and separated with ethyl acetate.
  • the aqueous layer was basified with 1M aqueous sodium hydroxide and extracted with ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound as a yellow oil (24.7 mg, yield: 76%).
  • the reaction mixture was mixed with saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate.
  • the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the resulting yellow oil was used for the next step without further purification.
  • the reaction mixture was mixed with water and 1M hydrochloric acid and separated with ethyl acetate.
  • the resulting aqueous layer was basified with 1M aqueous sodium hydroxide and extracted with ethyl acetate.
  • the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the resulting residue containing the title compound was used for the next step without further purification.
  • the title compound was obtained as a white solid (3.1 mg, yield: 23% (2 stages)) substantially in the same manner as in Synthetic Example 36 except that methanesulfonyl chloride was used instead of 2,2,2-trifluoroethanesulfonyl chloride.
  • the reaction mixture was mixed with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • sodium hydride 55 wt % dispersion in liquid paraffin, 5.8 mg, 0.135 mol
  • the reaction mixture was mixed with water and extracted with ethyl acetate.
  • the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the reaction mixture was mixed with aqueous sodium hydroxide and chloroform until the aqueous layer was adjusted to pH 5, and the mixture was extracted with chloroform.
  • the aqueous layer was adjusted to pH 9 to 10 with additional amount of aqueous sodium hydroxide and the mixture was extracted with chloroform.
  • the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a mixture (6.3 mg) containing the title compound.
  • the reaction mixture was azeotropically distilled with toluene and mixed with methanol (1.0 mL) and ethylenediamine (50 ⁇ L), followed by stirring at room temperature for 1.5 hours.
  • the mixture was mixed with additional amount of ethylenediamine (150 ⁇ L), and the mixture was stirred at room temperature for 1.5 hours.
  • the reaction mixture was mixed with water and extracted with ethyl acetate.
  • the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium hydrogencarbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • dichloromethane 2 mL
  • trifluoroacetic acid 2 mL

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Rheumatology (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
US14/764,652 2013-02-08 2014-02-05 Tricyclic pyrrolopyridine compound, and JAK inhibitor Active US9475813B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
JP2013023650 2013-02-08
JP2013-023650 2013-02-08
JP2013-066124 2013-03-27
JP2013066124 2013-03-27
PCT/JP2014/052700 WO2014123167A1 (fr) 2013-02-08 2014-02-05 Composé pyrrolopyridine tricyclique et inhibiteur de jak

Publications (2)

Publication Number Publication Date
US20150368245A1 US20150368245A1 (en) 2015-12-24
US9475813B2 true US9475813B2 (en) 2016-10-25

Family

ID=51299759

Family Applications (1)

Application Number Title Priority Date Filing Date
US14/764,652 Active US9475813B2 (en) 2013-02-08 2014-02-05 Tricyclic pyrrolopyridine compound, and JAK inhibitor

Country Status (6)

Country Link
US (1) US9475813B2 (fr)
EP (1) EP2955181B1 (fr)
JP (1) JP6248948B2 (fr)
ES (1) ES2755130T3 (fr)
TW (1) TWI626241B (fr)
WO (1) WO2014123167A1 (fr)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2015260349B2 (en) * 2014-05-14 2019-02-21 Nissan Chemical Industries, Ltd. Tricyclic compound and JAK inhibitor
JOP20190144A1 (ar) 2016-12-16 2019-06-16 Janssen Pharmaceutica Nv إيميدازو بيرولو بيريدين كمثبطات لعائلة jak الخاصة بإنزيمات الكيناز
CN107298680A (zh) * 2017-07-12 2017-10-27 海门华祥医药科技有限公司 一种4‑氯‑7‑氮杂吲哚的生产工艺
WO2019090158A1 (fr) * 2017-11-03 2019-05-09 Aclaris Therapeutics, Inc. Inhibiteurs de jak à base de pyrrolopyrimidine substituée et leurs procédés de fabrication et d'utilisation
TW202016110A (zh) 2018-06-15 2020-05-01 比利時商健生藥品公司 Ｊａｋ激酶家族之小分子抑制劑
EA202192575A1 (ru) 2019-03-21 2022-01-14 Онксео Соединения dbait в сочетании с ингибиторами киназ для лечения рака
EP3969458A4 (fr) 2019-05-13 2023-05-17 Borah, Inc. Composés chimiques
US20220401436A1 (en) 2019-11-08 2022-12-22 INSERM (Institute National de la Santé et de la Recherche Médicale) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
EP4065586A1 (fr) * 2019-11-26 2022-10-05 F. Hoffmann-La Roche AG Composés 1,8-naphtyridin-2-one pour le traitement d'une maladie auto-immune
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
WO2022155202A1 (fr) * 2021-01-13 2022-07-21 Schrödinger, Inc. Hétérocycles fusionnés et leurs utilisations

Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001042246A2 (fr) 1999-12-10 2001-06-14 Pfizer Products Inc. Composes a base de pyrrolo[2,3-d]pyrimidine
WO2007007919A2 (fr) 2005-07-14 2007-01-18 Astellas Pharma Inc. Nouveaux composes
WO2007077949A1 (fr) 2005-12-28 2007-07-12 Astellas Pharma Inc. Inhibiteurs heterocycliques de la janus kinase 3
WO2007134259A2 (fr) 2006-05-11 2007-11-22 Irm Llc Composés inhibiteurs de protéines kinases et compositions comprenant de tels composés
WO2008084861A1 (fr) 2007-01-12 2008-07-17 Astellas Pharma Inc. Composé de pyridine condensée
WO2009152133A1 (fr) 2008-06-10 2009-12-17 Abbott Laboratories Nouveaux composés tricycliques
WO2010119875A1 (fr) 2009-04-14 2010-10-21 アステラス製薬株式会社 Dérivé de pyrrolopyridine condensé
WO2011045702A1 (fr) 2009-10-15 2011-04-21 Pfizer Inc. Composés pyrrolo[2,3-d]pyrimidine
WO2011068899A1 (fr) 2009-12-01 2011-06-09 Abbott Laboratories Nouveaux composés tricycliques
WO2011068881A1 (fr) 2009-12-01 2011-06-09 Abbott Laboratories Composés tricycliques innovants
WO2011075334A1 (fr) 2009-12-18 2011-06-23 Pfizer Inc. Composés pyrrolo[2,3-d]pyrimidines
WO2011086053A1 (fr) 2010-01-12 2011-07-21 F. Hoffmann-La Roche Ag Composés hétérocycliques tricycliques, leurs compositions et procédés d'utilisation
WO2012085176A1 (fr) 2010-12-23 2012-06-28 F. Hoffmann-La Roche Ag Composés pyrazinones tricycliques, leurs compositions et leurs procédés d'utilisation en tant qu'inhibiteurs de janus kinase
WO2012127506A1 (fr) 2011-03-22 2012-09-27 Advinus Therapeutics Limited Composés tricycliques substitués; compositions et applications médicinales correspondantes
WO2012149280A2 (fr) 2011-04-29 2012-11-01 Abbott Laboratories Nouveaux composés tricycliques
WO2013024895A1 (fr) 2011-08-12 2013-02-21 Nissan Chemical Industries, Ltd. Composés hétérocycliques tricycliques et inhibiteurs de jak

Patent Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001042246A2 (fr) 1999-12-10 2001-06-14 Pfizer Products Inc. Composes a base de pyrrolo[2,3-d]pyrimidine
WO2007007919A2 (fr) 2005-07-14 2007-01-18 Astellas Pharma Inc. Nouveaux composes
WO2007077949A1 (fr) 2005-12-28 2007-07-12 Astellas Pharma Inc. Inhibiteurs heterocycliques de la janus kinase 3
WO2007134259A2 (fr) 2006-05-11 2007-11-22 Irm Llc Composés inhibiteurs de protéines kinases et compositions comprenant de tels composés
US20100048552A1 (en) 2006-05-11 2010-02-25 Irm Llc Compounds and compositions as protein kinase inhbitors
WO2008084861A1 (fr) 2007-01-12 2008-07-17 Astellas Pharma Inc. Composé de pyridine condensée
WO2009152133A1 (fr) 2008-06-10 2009-12-17 Abbott Laboratories Nouveaux composés tricycliques
US20130216497A1 (en) 2008-06-10 2013-08-22 Neil Wishart Novel tricyclic compounds
WO2010119875A1 (fr) 2009-04-14 2010-10-21 アステラス製薬株式会社 Dérivé de pyrrolopyridine condensé
WO2011045702A1 (fr) 2009-10-15 2011-04-21 Pfizer Inc. Composés pyrrolo[2,3-d]pyrimidine
WO2011068881A1 (fr) 2009-12-01 2011-06-09 Abbott Laboratories Composés tricycliques innovants
WO2011068899A1 (fr) 2009-12-01 2011-06-09 Abbott Laboratories Nouveaux composés tricycliques
WO2011075334A1 (fr) 2009-12-18 2011-06-23 Pfizer Inc. Composés pyrrolo[2,3-d]pyrimidines
WO2011086053A1 (fr) 2010-01-12 2011-07-21 F. Hoffmann-La Roche Ag Composés hétérocycliques tricycliques, leurs compositions et procédés d'utilisation
US20110201593A1 (en) 2010-01-12 2011-08-18 Genentech, Inc. Tricyclic heterocyclic compounds, compositions and methods of use thereof
WO2012085176A1 (fr) 2010-12-23 2012-06-28 F. Hoffmann-La Roche Ag Composés pyrazinones tricycliques, leurs compositions et leurs procédés d'utilisation en tant qu'inhibiteurs de janus kinase
WO2012127506A1 (fr) 2011-03-22 2012-09-27 Advinus Therapeutics Limited Composés tricycliques substitués; compositions et applications médicinales correspondantes
WO2012149280A2 (fr) 2011-04-29 2012-11-01 Abbott Laboratories Nouveaux composés tricycliques
US20120330012A1 (en) 2011-04-29 2012-12-27 Abbott Laboratories Novel Tricyclic Compounds
WO2013024895A1 (fr) 2011-08-12 2013-02-21 Nissan Chemical Industries, Ltd. Composés hétérocycliques tricycliques et inhibiteurs de jak

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
Elizabeth Kudlacz, at al., "The JAK-3 inhibitor CP-690550 is a potent anti-inflammatory agent in a murine model of pulmonary eosinophilia", European Journal of Pharmacology, vol. 582, 2008, pp. 154-161.
International Search Report issued Mar. 4, 2014, in PCT/JP2014/052700, filed Feb. 5, 2014.
J. Staerk, et al., "JAK2, the JAK2 V617F mutant and cytokine receptors", Pathologie Biologie, vol. 55, 2007, pp. 88-91.
Joel M. Kremer, et al., "The Safety and Efficacy of a JAK Inhibitor in Patients With Active Rheumatoid Arthritis", Arthritis & Rheumatism, vol. 60, No. 7, Jul. 2009, pp. 1895-1905.
John J. O'Shea, et al., "Cytokine Signaling in 2002: New Surprises in the Jak/Stat Pathway", Cell, vol. 109, Apr. 2002, pp. S121-S131.
Jong-Ha Yoo, et al., "JAK2 V617F/C618R mutation in a patient with polycythemia vera: A case study and review of the literature", Cancer Genetics and Cytogenetics, vol. 189, 2009, pp. 43-47.
Katsutoshi Ozaki, et al., "A Critical Role for IL-21 in Regulating Immunoglobulin Production", Science, vol. 298, Nov. 22, 2002, pp. 1630-1634.
Mg Boy, et al., "Double-Blind, Placebo-Controlled, Dose-Escalation Study to Evaluate the Pharmacologic Effect of CP-690,550 in Patients With Psoriasis", Journal of Investigative Dermatology, vol. 129, 2009, pp. 2299-2302.
Paolo Macchi, et al., "Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID)", Letters to Nature, vol. 377, Sep. 7, 1995, pp. 65-68.
Paul S. Changelian, et al., "Prevention of Organ Allograft Rejection by a Specific Janus Kinase 3 Inhibitor", Science, vol. 302, Oct. 31, 2003, pp. 875-878.
Peter J. Murray, "The JAK-STAT Signaling Pathway: Input and Output Integration", The Journal of Immunology, vol. 178, 2007, pp. 2623-2629.
Sarah M. Russell, et al., "Mutation of Jak3 in a Patient with SCID: Essential Role of Jak3 in Lymphoid Development", Science, vol. 270, Nov. 3, 1995, pp. 797-800.
William Vainchenker, et al., "JAKs in pathology: Role of Janus kinases in hematopoietic malignancies and immunodeficiencies", Seminars in Cell & Developmental Biology, vol. 19, 2008, pp. 385-393.

Also Published As

Publication number Publication date
TW201446766A (zh) 2014-12-16
EP2955181B1 (fr) 2019-10-30
WO2014123167A1 (fr) 2014-08-14
ES2755130T3 (es) 2020-04-21
US20150368245A1 (en) 2015-12-24
EP2955181A4 (fr) 2016-11-02
EP2955181A1 (fr) 2015-12-16
JPWO2014123167A1 (ja) 2017-02-02
JP6248948B2 (ja) 2017-12-20
TWI626241B (zh) 2018-06-11

Similar Documents

Publication Publication Date Title
US9475813B2 (en) Tricyclic pyrrolopyridine compound, and JAK inhibitor
US9556187B2 (en) Substituted pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidines and JAK inhibitors comprising the same
US8372854B2 (en) Pyrrolo[2,3-D]pyrimidine compounds
JP5629324B2 (ja) ピロロ［２，３−ｄ］ピリミジン化合物
CA3084777C (fr) Derives amino-fluoropiperidines utilises en tant qu'inhibiteur de kinase
AU2018394996B2 (en) Amino-methyl piperidine derivative as kinase inhibitor
US10385052B2 (en) Tricyclic compound and JAK inhibitor
NZ709835B2 (en) Tricyclic heterocyclic compounds and jak inhibitors

Legal Events

Date Code Title Description
AS Assignment

Owner name: NISSAN CHEMICAL INDUSTRIES, LTD., JAPAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:TAKAHASHI, KEIJI;WATANABE, TSUNEO;HAYASHI, KEISHI;AND OTHERS;SIGNING DATES FROM 20150608 TO 20150612;REEL/FRAME:036215/0851

STCF Information on status: patent grant

Free format text: PATENTED CASE

CC Certificate of correction
MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1551); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Year of fee payment: 4